Research has provided considerable evidence that the risk for alcoholism is influenced by genetic factors. The long term goal of this project is to provide novel targets for alcohol treatment by identifying genes that influence alcohol preference. The objective of this proposal is to identify and characterize the strong candidate genes in the fine mapped chromosome (Chr) QTL regions in the selectively outbred high alcohol drinking (HAD) and low alcohol drinking (LAD) rats and the high alcohol preferring (HAP) and low alcohol preference (LAP) mice. Our proposal to fine map the QTL regions will be accomplished by applying a novel, multipoint, identity by descent approach well suited to analyses of noninbred populations. Following fine mapping of the QTL intervals, the results of microarray analyses and the utilization of bioinformatic resources will allow us to determine which of the differentially expressed genes are within the narrowed QTL intervals. The differential expression of these genes will be confirmed by quantitative Real-Time PCR (qRT-PCR) analysis. Strong candidate genes will then be tested for protein expression differences by using quantitative Western Blot analyses. Finally, we will identify coding and/or regulatory sequence changes that influence the expression of the differentially expressed candidate genes and determine functional significance by transient transfection reporter assays. The proposed research in this application will take advantage of unique noninbred animal models in combination with new and innovative analyses to narrow the QTL regions and identify candidate genes that underlie alcohol preference.